Astrocyte TrkB.T1 Deficiency Disrupts Glutamatergic Synaptogenesis and Astrocyte–Synapse Interactions

Abstract

Perisynaptic astrocyte processes (PAPs) contact pre- and postsynaptic elements to provide structural and functional support to synapses. Accumulating research demonstrates that the contact of synapses by PAPs is critical for synapse formation, stabilization, and plasticity. The specific signaling pathways that govern these astrocyte–synapse interactions, however, remain to be elucidated. Herein, we demonstrate the role of the astrocyte TrkB.T1 receptor, a truncated isoform of the canonical receptor for brain-derived neurotrophic factor (BDNF), in modulating astrocyte–synapse interactions and excitatory synapse development. Neuron–astrocyte coculture studies revealed that loss of astrocyte TrkB.T1 disrupts the formation of PAPs. To elucidate the role of TrkB.T1 in synapse development, we conditionally deleted TrkB.T1 in astrocytes in mice of either sex. Synaptosome preparations were employed to probe for TrkB.T1 localization at the PAP, and confocal three-dimensional microscopy revealed a significant reduction in synapse density and astrocyte–synapse interactions across development in the absence of astrocytic TrkB.T1. Furthermore, conditional knock-out of astrocyte TrkB.T1 alters motor learning and experience-dependent astrocyte–synapse interactions. These findings suggest that BDNF/TrkB.T1 signaling in astrocytes is critical for normal excitatory synapse formation in the cortex and that astrocyte TrkB.T1 serves a requisite role in astrocyte synapse interactions. Overall, this work provides new insights into the molecular mechanisms of astrocyte-mediated synaptogenesis.